PL168968B1 - Method of manufacturing an antitussive drug - Google Patents

Abstract

The subject invention involves antitussive pharmaceutical compositions for the peroral administration of dextromethorphan, the composition being at a pH of from about 8 to about 11.

Description

The present invention relates to a method for the preparation of an agent for the treatment or prevention of cough in humans by oral administration, which consists in combining dextromethorphan with carriers and optionally other antitussive agents. The agent prepared by the method of the invention allows for the rapid achievement of therapeutic levels of dextrometomorphan in the body.

Dextromethorphan (racemetorfan), or 3-methoxy-17-methylmorphinan, is described in the Merck Index, 10th Edition (1983), Publisher M. Windholz, No. 8009, p. 1170 as an antitussive agent.

Dextramethomorphan hydrobromide is widely used as an antitussive agent in commercial products described in Physician's Desk Reference for Nonprescription Drugs, 11th Edition (1990), edited by E.R. Barnhardt, p. 306 and in Physician's Desk Reference, 44th Edition (1990), edited by E.R. Barnhardt, p. 309, such as: Glenbrook's Bayer Children's Cough Syrup, Parke-Davis's Benylin DM. Benelin Expectorant by Parke-Davis. Cerose-DM by Wyeth-Ayerst, Cheracol D Cough Formula by Upjohn, Cheracol Plus Head Cough / Cold Formula by Upjohn, Cough Formula Comtrex by Bristol-Myers Products. Comtrex Multi-Symptom Cold Reliever (tablets, liquids, liquid gels) by Bristol-Myers Products, Contac Cough Formula by SmithKline Consumer, Contac Cough and Sore Throat Formula by SmithKline Consumer, Contac Jr. Children's Cold Medicine by SmithKline Consumer, Contac Severe Cold Formula Caplets by SmithKline Consumer, Dimacol Caplets by Robins, Dorcol Children's Cough Syrup by Sandoz Consumer, Hold by SmithKline Beecham, Naldecon DX Adult Liquid by Bristol Laboratories. Naldecon DX Childrens Syrup by Bristol Laboratories, Naldecon DX Pediatric Drops by Bristol Laboratories, Naldecon Senior DX Cough / Cold Liquid by Bristol Laboratories, Novahistine DMX by Lakeside Pharmaceuticals, Pediacare Cough-Cold Formula Liquid and Chewable Tablets by McNeil Consumer Products, Pediacare Night Rest Cough-Cold Formula Liquid by McNeil Consumer Products, Robitussin Night Relief by Robins, Robitussin-CF by Robins, Robitussin-DM by Robins. Scot-Tussin Sugar-Free DM Cough and Cold

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Medicine by Scot-Tussin, Snaplets-DM by Baker Cummins Pharmaceuticals, SnapletsMulti by Baker Cummins Pharmaceuticals, St. Joseph Cough Suppressant for Children by Plow, St. Joseph Nighttime Cold Medicine by Plow, Sucrets Cough Control Formula by SmithKline Beecham, Sudafed Cough Syrup by Burroughs Wellcome, Triaminic Night Light by Sandoz Consumer, Triaminic-DM Syrup by Sandoz Consumer, Triaminicol Multi-Symptom Cold Tablets by Sandoz Consumer, Triaminicol Multi- Symptom Relief by Sandoz Consumer, Tylenol Cold Mediction Caplets and Tablets by McNeil Consumer Products, Tylenol Cold Medication Liquid by McNeil Consumer Products, Tylenol Cold Medication No Drowsiness Formula Caplets by McNeil Consumer Products. Vicks Children's Cough Syrup by Richardson-Vicks. Inc., Vicks Children's NyQuil by Richardson-Vicks, Inc., Vicks Cough Silencers Cough Drops by Richardson-Vicks. Inc., Vicks Daycare Daytime Cold Medicine Caplets of Richardson-Vicks. Inc., Vicks Daycare Multi-Symptom Colds Medicine Liquid by Richardson-Vicks, Inc., Vicks Formula 44 Cough Control Discs by Richardson-Vicks, Inc., Vicks Formula 44 Cough Medicine by Richardson-Vicks, Inc., Vicks Formula 44D Decongestant Cough Medicine by Richardson-Vicks, Inc., Vicks Formula 44M Multi-Symptom Cough Medicine by Richardson-Vicks, Inc., Vicks NyQuil Nighttime Cold Medicine-Original and Cherry Flavor by Richardson-Vicks, Inc., Vicks Pediatric Formula 44 Cough Medicine from Richardson-Vicks, Inc., Vicks Pediatric Formula 44 Cough and Cold Medicine by Richardson-Vicks, Inc., Vicks Pediatric Formula 44 Cough and Congestion Medicine by Richardson-Vicks, Inc., Ambenyl-D Decongestant Cough Formula by Forest Pharmaceuticals, Bromareast DX Cough Syrup by Warner Chilcott, BromFed-DM Cough Syrup by Muro, Codimal DM by Central Pharmaceuticals, Dimetane-DX Cough Syrup by Robins, Guaifenesin w / D-Methorphan Hydrobromide Syrup by Lederle, Humibi d dM Tablets by Adams, IoTuss-DM Liquid by Muro, Medi-Tuss DM by Warner Chilcott, Phenergan with Dextromethorphan by Wyeth-Ayerst, Poly-Histine DM Syrup by Bock, Quelidrine Syrup by Abbott, Rondec-DM Oral Drops by Ross, Rondec dM Syrup by Ross, Tusibron-DM by RAM Laboratories, Tussar DM by Rorer Pharmaceuticals and Tussi-Organidin DM Liquid by Wallace, Delsym Cough Suppressant Syrup by McNeil Consumer contains dextromethorphan polistirex as an antitussive agent. All of the above commercial dextromethorphan-containing products are believed to be present in the composition at approximately neutral or below pH.

A.H. Beckett and E.G. Triggs reports in Buccal Absorption of Basic Drugs and Its Application as an InVivo Model of Passive Drug Transfer Through Lipid Membranes, Journal of Pharmaceutics and Pharmacology, vol.19, Supplement (1967), pp. 315-415 that buccal absorption of many drugs is significantly increased from compositions with higher pH when these compositions are held and turned in the mouth for 5 minutes. Dextromethorphan is not described as one such drug in the work of Beckett and Triggs. The discovery of Beckett and Triggs is not expected to be particularly useful for liquid products that are not generally held in the mouth but are swallowed quickly, or even for solid products such as diamond-shaped lozenges that are dissolved in the mouth and then swallowed quickly.

In U.S. Patent No. US Am. No. 4,892,877 to Sorrentino, issued Jan. 9, 1990, discloses a liquid antitussive containing dextromethorphan and phenol which has a pH of 5-9. US Am. No. 4,427,681 of Munshi, filed January 24, 1984, describes thixotropic antitussive agents containing dextromethorphan and Avicel ^R RC-591.

The subject of the invention is a method for the preparation of an agent for the treatment or prevention of cough in humans by oral administration, which consists in combining dextromethorphan with carriers and other antitussive agents, and is characterized in that the pH value of the agent is set in the range from 9 to 11. Agents prepared according to the method of The invention shows a faster antitussive effect than the commercially available agents.

The pharmaceutical compositions for oral administration according to the invention contain a safe and effective amount of dextromethorphan and an orally acceptable pharmaceutical carrier, and have a pH of about 8 to about 11.

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Preferred pharmaceutical compositions for oral administration according to the invention contain a safe and effective amount of dextromethorphan, safe and effective amounts of antitussive / anti-cold drugs other than phenol, and an orally acceptable pharmaceutical carrier, having a pH of about 9 to about 11.

Other preferred pharmaceutical compositions for oral administration according to the invention comprise a safe and effective amount of dextromethorphan, a safe and effective amount of phenol, and an orally acceptable pharmaceutical carrier, having a pH greater than 9 to about 11.

The process of the invention includes a method of preparing compositions containing a safe and effective amount of dextromethorphan and optionally other active drugs. The term safe and effective amount means an amount of active drug large enough to have a significant positive effect on the disease state being treated, but also small enough to avoid serious side effects (with a reasonable benefit-risk ratio) as determined by medical judgment. The safe and effective amount of active drug can vary depending upon the condition being treated, the age and physical condition of the patient, the severity of the case, the duration of treatment, the type of concurrent therapy, and the like.

Dextromethorphan is known to exhibit pharmacological activity as an antitussive agent. The term dextromethorphan used in the description means racemetorphan or 3-methoxy-17-methylmorphinate (dl-cis-1,3,4,9,10,1 Oa-hexahydro-6-methoxy-11-methyl-2H10,4a-iminoethanophenanthrene):

CH

and pharmaceutically acceptable salts thereof. A preferred salt of dextromethorphan is hydrobromide.

The composition of the present invention preferably contains from about 1 mg to about 50 mg of dextromethorphan per dose, more preferably from about 2.5 mg to about 30 mg of dextromethorphan. The liquid compositions preferably contain from about 0.02% to about 1.5%, more preferably from about 0.05% to about 1%, most preferably from about 0.1% to about 0.3% dextromethorphan. A typical dose of a liquid antitussive is from about 1 ml to about 30 ml. A more typical dose of liquid cough syrup is from about 5 ml to about 20 ml, especially about 15 ml. The dose of the liquid antitussive spray is more typically from about 2 ml to about 5 ml, especially about 3.5 ml.

The compositions of the invention contain a safe and effective amount of dextromethorphan and an orally acceptable pharmaceutical carrier, and have a pH of from about 8 to about 11, preferably from about 8.4 to about 10, more preferably from about 8.5 to about 9.5. , most preferably about 9. Still other preferred agents of the present invention contain a safe and effective amount of dextromethorphan, a safe and effective amount of phenol, and an orally acceptable pharmaceutical carrier, and have a pH greater than 9 to about 11, preferably from about 9.5 to about 10, and also preferably from about 9.1 to about 9.5.

It has been found that the compositions of the present invention achieve therapeutic blood levels of dextromethorphan more quickly, maintain such therapeutic levels over a longer period of time, and / or higher peak blood levels, compared to known dextromorphan lower pH agents.

The compositions of the present invention preferably have an alkaline buffering capacity sufficient to counteract the alteration caused by the saliva and mucous membranes in the mouth and throat, whereby the agent admixed with the saliva maintains the pH within the previously stated range while in the mouth and throat. These agents preferably have a buffering capacity of at least about 0.01 meq of base per one unit dose, preferably from about 0.05 mEq to about 2.5 mEq per unit dose, most preferably from about 0.1 mEq to about 1 .5 mEq per unit dose.

In the process of the invention, a pharmaceutically acceptable carrier is used, preferably one containing a pharmaceutically acceptable buffering system. Non-limiting examples of pharmaceutically acceptable buffering systems useful in the compositions of the invention include mixtures of monohydrogen and dihydrogen phosphate, buffer systems composed of sodium hydroxide and glycine, and buffers composed of carbonate and bicarbonate. Preferred buffer systems useful in the method of the invention are phosphate buffers.

A preferred component of the carrier used in the process of the invention is microcrystalline cellulose or a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose. Microcrystalline cellulose and mixtures thereof with sodium carboxymethylcellulose are available from FMC Corporation under the trade name Avicel®. In such mixtures it is preferred that the ratio of microcrystalline cellulose to sodium carboxymethyl cellulose is from about 20: 1 to about 1: 1, more preferably from about 15: 1 to about 3: 1, most preferably from about 10: 1 to about 5: 1.

A preferred mixture of microcrystalline cellulose and sodium carboxymethyl cellulose is Avivel® RC591, a commercially available microcrystalline cellulose manufactured by FMC Corporation, Food and Pharmaceutical Products Division, Philadelphia, Pennsylvania. Avicel® is a colloidal form of approximately 89% microcrystalline cellulose gel mixed with approximately 11% sodium carboxymethyl cellulose and dried. The product is easily dispersible in water. It is insoluble in water, organic solvents and dilute acids. It is partially soluble in dilute bases. It has the following chemical and physical properties: loss on drying - less than 6% in transit; heavy metals - less than 10 parts per million; viscosity of 1.2% solution - 65 ± 1%; particle size less than 0.1% retained on 60 mesh screen, less than 20% retained on 325 mesh screen. The average particle size of about 28 microns, the bulk density of the packing of light is 1946 kg / m ³ and in close about 2735 kg / m. The specific gravity is 1.55, the ash content is about 2%, the pH of the 2% slurry in water is 6-8. The product is further described in the bulletin L-318 fMc Corporation Avicel® RC-CL Microcrystalline Celluloze.

The amount of microcrystalline cellulose or its mixture with sodium carboxymethylcellulose in the compositions of the present invention is preferably from about 0.5% to about 3%, more preferably from about 1% to about 2%, most preferably about 1.5%.

The compositions according to the invention are intended for oral administration. Examples of such agents are preferably liquid agents, in particular aqueous agents, such as syrups, elixirs, suspensions, sprays and drops. Solid agents that are dissolved or chewed in the mouth are also preferred, such as rhombolide lozenges, diamond chewable lozenges, powders, and chewable tablets. The pH of such solid forms is determined by dissolving them in artificial saliva at a concentration of 10% and measuring the pH of the resulting solution or suspension. The preparation of artificial saliva is described by T. Fusayema, T. Katayori and S. Nomoto in Artificial Saliva, Journal of Dental Research, 42 (1963), pp. 1183-1197.

Dextromethorphan is relatively insoluble in the pH range of the agent of the invention. Therefore, it is preferable to add appropriate amounts of one or more cosolvents to the carrier to dissolve the dextromethorphan in the formulation and in the oral cavity. Preferred co-solvents for this purpose are ethanol, propylene glycol, polyethylene glycol, glycerin and sorbitol, more preferably ethanol, propylene glycol and glycerin.

In the liquid composition according to the invention, the carrier preferably comprises some of the following optional substances: water; sweetening agents such as sucrose, corn syrup, invert sugar, dextrose, sodium saccharinate, aspartame, sorbitol, honey and magnasweet; flavorings such as menthol, anethole, camphor, thymol, methyl salicylate, eucalyptus oil and peppermint oil; other flavorings; means

Thickeners such as carboxymethyl cellulose, sodium carboxymethyl cellulose, cellulose, glycerin and polyethylene glycol; dyes; preservatives, such as sodium benzoate, cetylpyridinium chloride; various substances such as potassium sorbate, sodium chloride, titanium dioxide, polysorbate 80, sodium citrate, sodium bicarbonate, sodium hydroxide, aluminum hydroxide, and magnesium hydroxide.

In solid formulations of the inventive composition, the carrier preferably comprises one or more of the additional substances mentioned above for liquid preparations, and may optionally include the following: solid diluents, binders, dispersants, darkening agents such as silicon dioxide. , talc, polyvinylpyrrolidone, kaolin, dicalcium phosphate, calcium sulfate, lactose starch; as well as other additives such as acacia, capsicin, mannitol, sodium alginate, alginic acid, guar gum, veegum, gelatin, ethyl cellulose, magnesium stearate, bentonite and sodium lauryl sulfate.

The compositions according to the invention may also contain one or more other active ingredients useful in the treatment of cough and / or cold (antitussive / anti-cold drugs). Antitussive / anti-cold drugs commonly used in combination with antitussive agents in commercial products are preferred. Antitussive / anti-cold drugs useful in the formulations of the present invention include antihistamines, bronchodilators, decongestants, expectorants, local anesthetics, and anti-inflammatory / analgesic drugs. Examples of preferred such drugs and the preferred amounts per dose of the agents of the invention are: antihistamines such as chlorpheniramine (preferably from about 1 mg to about 8 mg, more preferably from about 2 mg to about 4 mg) and salts thereof (e.g. maleate), diphenhydramine (preferably from about 6 mg to about 50 mg, more preferably from about 12 mg to about 25 mg) and its salts (e.g., hydrochloride), brompheniramine (preferably from about 1 mg to about 8 mg, more preferably from about 2 mg to about 4 mg) and its salts, doxylamine (preferably from about 2 mg to about 20 mg, more preferably from about 6 mg to about 12 mg) and its salts (e.g. succinate), triprolidine (preferably from about 0.5 mg up to about 4 mg, more preferably from about 1 mg to about 3 mg), and salts thereof (e.g. hydrochloride); bronchodilators such as ephedrine (preferably from about 5 mg to about 50 mg, more preferably from about 10 mg to about 25 mg) and its salts (e.g. hydrochloride, sulfate); decongestants such as pseudoephedrine (preferably from about 10 mg to about 100 mg, more preferably from about 30 mg to about 60 mg) and its salts (e.g. hydrochloride), phenylephrine (preferably from about 2 mg to about 20 mg, more preferably from about 5 mg to about 10 mg) and its salts (e.g. hydrochloride), phenylpropanolamine (preferably from about 5 mg to about 50 mg, more preferably from about 12 mg to about 25 mg) and its salts (e.g. hydrochloride); expectorants such as guaifenesin (preferably from about 50 mg to about 400 mg, more preferably from about 100 mg to about 200 mg); local anesthetics such as benzocaine (preferably from about 1 mg to about 25 mg, more preferably from about 2 mg to about 15 mg), phenol (preferably from about 10 mg to about 150 mg, more preferably from about 20 mg to about 50 mg ), dyclonin (preferably from about 1 mg to about 10 mg, more preferably from about 2 mg to about 4 mg) and its salts (e.g. hydrochloride), lidocaine (preferably from about 2 mg to about 20 mg, more preferably from about 4 mg to about 10 mg) and its salts (e.g. hydrochloride), butacaine (preferably from about 5 mg to about 50 mg, more preferably from about 10 mg to about 20 mg) and its salts (e.g. sulfate, hydrochloride), benzyl alcohol ( preferably from about 50 mg to about 750 mg, more preferably from about 100 mg to about 500 mg), dibucaine (preferably from about 0.1 mg to about 4 mg, more preferably from about 0.5 mg to about 2 mg) and salts thereof (e.g. hydrochloride), tetracaine (preferably from about 0.1 mg to about 4 mg, more preferably from about 0.5 mg to about mg) and its salts (e.g. hydrochloride), sodium phenate (k preferably from about 10 mg to about 150 mg, more preferably from about 20 mg to about 50 mg), salicylic alcohol (preferably from about 20 mg to about 200 mg, more preferably from about 50 mg to about 100 mg), hexylresorcinol (preferably from about 1 mg to about 10 mg, preferably from about 2 mg to about 4 mg), and menthol (preferably from about 2 mg to about 50 mg, more preferably from about 5 mg to about 25 mg); anti-inflammatory / analgesic drugs such as acetaminophen (preferably from about 60 mg to about

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1000 mg, more preferably from about 300 mg to about 650 mg), ibuprofen (preferably from about 100 mg to about 800 mg, more preferably from about 200 mg to about 400 mg) and its salts (e.g. sodium), aspirin (preferably from about 75 mg to about 1000 mg, more preferably from about 300 mg to about 650 mg) and its salts (e.g. sodium) and naproxen (preferably from about 75 mg to about 500 mg, more preferably from about 125 mg to about 300 mg) and its salts (e.g. sodium).

The agents of the invention are used to treat or prevent cough in humans or lower animals by the oral administration of an agent. The daily dose of dextromethorphan is preferably from about 0.1 mg / kg to about 10 mg / kg body weight, more preferably from about 0 mg / kg. , 5 mg / kg to about 5 mg / kg, or more preferably from about 1 mg / kg to about 3 mg / kg. It is preferred to orally administer the dextromethorphan-containing agent to patients from about 1 to about 10 times daily, more preferably from about 2 to about 8 times daily, or more preferably from about 3 to about 6 times daily.

The following examples serve to illustrate the process of the invention. Liquid preparations and diamond-shaped pellets are prepared by conventional methods.

Example I. Preparation of a liquid antitussive preparation

Ingredients Amount nn dose 1 5 ml

Dextromethorphan HBr 30.00 mg

Propylene glycol 1.74 g

Ethanol (95%) 1.50 ml

Menthol (natural) 12 mo mg

Eucalyptus oil 7.5ο mg

Flavorings 0.05 ml

Sucrose 7.65 g

Carboxymethylcellulose (CMC) 0.00 mg

Microcrystalline cellulose and sodium CMC (Avicel® RC591, FMC) 187.50 mg

Polysorbate 80 0.00 mg

Glycerin 300.00 mg

Sorbit 300.00 mg

Red F, D and C No. 40 3.00 mg

Glycine 28.20 mg

Sodium hydroxide 0.00 mg

Purified water and rubbed

First, three separate liquid phases were prepared by mixing together the following ingredients: (1) aztrooethorphan hydrobromide, propylene glycol, ethanol, oentol, eucalyptus oil, and flavorings; (2) sucrose, CMC, Avicel, polysorbate 80, glycerin, sorbitol, and some water; and (3) a dye, glycine, sodium hydroxide, and some water. The three liquid phases were mixed with the remaining amount of water to obtain a liquid antitussive having a pH of 8-11.

Example II. Manufacture of a liquid cough suppressant. Proceeding similarly to Example 1, a liquid formulation was prepared with a pH in the range 8-11 with the following composition:

Ingredient

Dextromethorphan HBr

Propylene glycol

Ethanol (95%)

Polyethylene glycol (Carbowax 400) Flavorings Red F, D and C No 40 Dibasic sodium phosphate Sodium saccharinate Purified water

Take a dose of 11 ml

15.00 mg

777.0 ml 1.50 ml

750.00 mg 0.05 ml 5.10 mg

231.00 mg

22.50 mg as needed

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Example III. Preparation of a liquid antitussive preparation. Proceeding similarly to Example 1, a liquid formulation with a pH of 8-11 was prepared with the following composition:

Ingredient

Dextromethorphan HBr Propylene glycol Ethanol (95%)

Menthol (natural)

Eucalyptus oil

Flavorings

Red F, D and C No. 40

Dibasic sodium phosphate

Sodium Saccharinate

Saccharose

Glycerine

Sodium hydroxide Purified water

Amount per dose of 15 ml

30.00 mg l, 74 g 1.55 ml

22.50 mg 7.50 mg 0.00 n / 5.10 mg

231.00 m g

30.00 mg 8.16 g

750.00 mg 3, (0) mg as needed

Example IV. Preparation of a liquid antitussive preparation. In a similar manner to Example 1, a liquid formulation was prepared with a pH in the range 8-11 with the following composition:

Components

Dextromethorphan HBr

Saccharose

Carboxymethyl Cellulose (CMC)

Microcrystalline cellulose and sodium cMc (Avicel® RC591, FMC) Polysorbate 80 Glycerine Sorbit

Red F, D and C No. 40

Dibasic sodium phosphate

Sodium hydroxide

Sodium Saccharinate

Propylene glycol

Ethanol (95%)

Menthol

Eucalyptus oil

Flavorings

Purified Water

Amount per dose of 15 ml

30.00 mg 8.16 g 7.50 mg

118.50 mg 3.00 mg

300.00 mg of 30 ° C. 00 mg

3.00 mg 231 /) 0 mg

3.60 mg

30.00 nm 1.71 g 1.10 nm

23.55) nm 7.55 nm 0.05 nm as needed

Example 5 Preparation of a liquid antitussive preparation. Proceeding similarly to Example 1, a liquid preparation was prepared with a pH in the range 9-11 with the following composition:

Ingredient

Amount per dose of 15 ml

Dextromethorphan HBr 23.00 nm

Sucrose 8.10 g

CMC 7.50 mg

Microcrystalline cellulose and sodium CMC (Avicel® RC591, FMC) 187.50 mg

Polysorbate 80 3.00 nm

Glycerin 300.0 mg

Sorbitol 300.0 mg

Red F, D and C No. 40 30) 0 irm

Dibasic sodium phosphate 231.00 nm

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Sodium hydroxide 5.00 mg

Sodium saccharinate 30.00 mg

Propylene glycol 1.74 g

Phenol 100.00 mg

Ethanol (95%) 1.5 ml

Menthol 22.5 mg

Eucalyptus oil 7.50 mg

Flavorings 0.05 ml

Purified water as needed

Example VI. Preparation of a liquid antitussive preparation. Proceeding similarly to Example 1, a liquid formulation was prepared with a pH in the range 8-11 with the following composition:

Amount per dose of 15 ml

30.00 mg 777.00 mg 1.50 ml 8.16 g

7.50 mg

187.50 mg 3.00 mg

300.00 mg

0.05 ml

5.10 mg 231.00 mg

3.60 mg

22.50 mg as needed

Ingredient

Dextromethorphan HBr Propylene glycol Ethanol (95%)

Saccharose

CMC

Microcrystalline cellulose and sodium CMC (Avicel® RC591, FMC)

Polysorbate 80

Glycerine

Flavorings Red F, D and C No 40 Dibasic sodium phosphate Sodium hydroxide Sodium saccharinate Purified water

Example VII. Preparation of a liquid antitussive preparation. Proceeding similarly to Example 1, a liquid formulation was prepared with a pH in the range 8-11 with the following composition:

Amount per dose of 15 ml

30.00 mg 1.74 g

1.50 ml 22.50 mg

7.50 mg 8.16 g 7.50 mg

187.50 mg 3.00 mg 0.05 ml 5.10 mg

231.00 mg

30.00 mg

300.00 mg

3.60 mg as needed

Ingredient

Dextromethorphan HBr Propylene glycol Ethanol (95%)

Menthol (natural)

Eucalyptus oil

Saccharose

CMC

Microcrystalline cellulose and sodium CMC (Avicel® RC591, FMC)

Polysorbate 80

Flavorings

Red F, D and C No. 40

Dibasic sodium phosphate

Sodium Saccharinate

Glycerine

Sodium hydroxide Purified water

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Example VIII. Preparation of a liquid antitussive preparation. In a similar manner to Example 1, a liquid formulation was prepared with a pH in the range 8-11 with the following composition:

Ingredient

Dextromethorphan HBr

Saccharose

Glycerine

Sorbit

Red F, D and C No 40 Dibasic sodium phosphate Sodium hydroxide Sodium saccharinate Propylene glycol Ethanol (95%)

Menthol

Eucalyptus oil Flavorings Purified water

Amount of the dose 15 ml

25.00 mg 8.16 g

300.00 mg 300.00 mg

3.00 mg 231.00 mg

3.60 mg 30.00 mg

1.7175

150 mm 22.50 mg

7.50 mg 0.05 γπΙ as needed

Example IX. Preparation of a liquid antitussive preparation. Proceeding similarly to Example 1, a liquid formulation was prepared having a pH in the range 9-11 with the following composition:

Ingredient

Dextromethorphan HBr

Saccharose

Glycerine

Sorbit

Red F, D and C No. 40 Dibasic sodium phosphate Sodium hydroxide Sodium saccharinate Propylene glycol Phenol

Ethanol (95%)

Menthol

Eucalyptus oil Flavorings Purified water

IIoo ^ nnddwkk 11 ml

30.00 mg 8.161

300.00 mg 300.00 mg

3.00 mg 221.0 mg

3.0 mg 30.00 mg

1.717 110.00 mg

150 na 22.0 mg

7.0 mg and 0.05 mg as needed

Example X. Preparation of a spray liquid antitussive preparation

Components

Dextromethorphan base

Propylene glycol

Ethanol (95%)

Polyethylene glycol (Carbowax 400) Sodium phosphate monobasic Sodium saccharinate Flavorings Red F, D and C No 40 Purified water

Amount per dose 3.5 ml

11.00 mg

0.70 mg 0.77 uds 0.70 na 8.40 mg 7.00 mg 0.14 nd 1J1 mg as needed

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A liquid formulation was prepared by mixing dextromethorphan base with propylene glycol. Subsequently, polyethylene glycol, alcohol flavorings and sodium saccharin were added portionwise while stirring. The monobasic sodium phosphate was added with stirring as a 10% solution in purified water. The dye solution in water and the remaining amount of water were also added while stirring. After mixing the ingredients, a formulation with a pH of 8-11 was obtained.

Example XI. Preparation of a liquid antitussive spray

Proceeding similarly to the example 10, a liquid antitussive spray was prepared with a pH in the range 9-11 with the following composition: ³

Ingredient

Dextromethorphan base

Propylene glycol

Ethanol (95%)

Polyethylene glycol (Carbowax 400)

Sodium sacchatinate

Flavorings

Red F, D and C No. 40

Phenol

Purified water

Amount per dose 3.5 ml

25.00 mg 0.70 ml 1.05 ml 0.70 ml 5.25 mg 0.012 .ml 1.19 mg 75.00 mg how much do you need

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Claims (6)

Patent claims A method of producing an agent for treating or preventing cough in humans by oral administration, which comprises combining dextromethorphan with carriers and other antitussive agents, wherein the pH of the agent is adjusted to a range from 9 to 11. 2. The method according to p. The method of claim 1, wherein the pH value of the agent is set in the range from 9 to 10. 3. The method according to p. The process of claim 1 or 2, wherein the formulation has a buffering capacity in the range of 0.05 to 2.5 meq of base per dose and a content of dextromethorphan of 2.5 to 30 mg per dose. 4. A method for the preparation of an agent for treating or preventing cough in humans by oral administration, which comprises combining dextromethorphan with carriers, characterized by adjusting the pH of the agent in the range from 8 to 11. 5. The method according to p. The process of claim 4, wherein the pH of the agent is set in the range from 8 to 10. 6. The method according to p. Process according to claim 4 or 5, characterized in that the agent has a buffering capacity in the range of 0.05 to 2.5 meq of base per dose and a content of dextromethorphan of 2.5 to 30 mg per dose.